Fentanyl, a synthetic opiate with a potency of 50 to 100 times that of morphine, is used clinically for the relief of pain in postsurgical patients as well as in terminal cancer patients. Pharmacodynamic studies after intramuscular administration of fentanyl have indicated that the peak analgesic effects generally occur at 1 hour after intravenous administration and are sustained for a shorter duration than morphine. The mean effective analgetic plasma concentrations of fentanyl are about 1 and 3 ng/ml for postoperative and intraoperative administration, respectively, although there is considerable intersubject variation. Up to 10 ng/ml plasma concentration of fentanyl yields similar analgetic effects in terminal cancer pain. The development of tolerance and physical dependence with repeated use of fentanyl is similar to that of other opioid drugs. However, lower initial dose may reduce the tolerance level of fentanyl.
The decline over time in fentanyl plasma concentration after intravenous administration appears to be triexponential with initial distribution phase followed by two elimination phases. The volume of distribution ranged from 4.4 to 59.7 liters, the terminal elimination half-life ranged from 141 to 853 minutes while total body clearance values ranged from 160 to 1530 ml/minute. The plasma protein binding in humans is reported to be 85%. Fentanyl is cleared primarily by metabolic routes in healthy volunteers and surgical patients, with renal clearance of fentanyl accounting for only 6% of the dose in volunteers.
Fentanyl (the citrate salt) is most frequently given intravenously or intramuscularly to achieve therapeutic effects. Fentanyl citrate is preferred for injection because of its aqueous solubility. Absorption of this compound via other routes is limited.
Conventional ways of delivering fentanyl have some major drawbacks. Although intravenous or intramuscular administration of fentanyl produces significant analgesic effects, it has to be given with excessive frequency because of high metabolic clearance. Oral absorption is variable and incomplete due to first-pass metabolism. Fentanyl also tends to cause respiratory depression in pain-relieving doses when administered intravenously.
Delivering fentanyl transdermally can minimize many of these problems, including the tendency for fentanyl underutilization by the physician. Side-effects which derive from the pulsed nature of delivery of parenteral dosage forms of fentanyl can be offset. In other words, the peak-and-valley of blood levels associated with discrete doses of drug can be eliminated. Moreover, the steady state plasma level of fentanyl can be maintained over the longer period of time by a constant flux of this drug through skin. Steady state plasma and tissue concentrations of fentanyl provide less toxicity risks than peak-and-valley concentrations resulting from injections.
European Patent No. 0171742 and U.S. Pat. No. 4,626,539 describe transdermal delivery of opioids and the use of various vehicles to enhance the penetration of opioids through skin. U.S. Pat. No. 4,588,580 describes specific systems for administering fentanyl. The particular device described in the patent uses ethanol as an enhancer and the fentanyl-ethanol mixture is contained in the reservoir in a fluid form. Using such a form complicates the procedure for manufacturing the device. Further, ethanol enhances the skin flux of fentanyl 3-4 fold as compared to fentanyl flux from water. That level of enhancement may not be sufficient to deliver an adequate amount of fentanyl transdermally through a reasonably-sized system because of high volume of distribution of fentanyl in the body. Also, the amount of fentanyl residing in the patented system at the completion of the prescribed wearing time is substantial. Since fentanyl is a restricted drug, significant amounts of residual fentanyl pose regulatory (DEA) problems and potential safety risks.